Efficient Strategies for Microglia Replacement in the Central Nervous System

Microglia are important immune cells in the central nervous system (CNS). Dysfunctions of gene-deficient microglia contribute to the development and progression of multiple CNS diseases. Microglia replacement by nonself cells has been proposed to treat microglia-associated disorders. However, some attempts have failed due to low replacement efficiency, such as with the traditional bone marrow transplantation approach. In this study, we develop three efficient strategies for microglia replacement: microglia replacement by bone marrow transplantation (mrBMT), microglia replacement by peripheral blood (mrPB), and microglia replacement by microglia transplantation (mrMT). mrBMT and mrPB allow microglia-like cells to efficiently replace resident microglia in the whole CNS. On the other hand, mrMT achieves microglia replacement in brain regions of interest. In summary, the present study offers effective tactics for microglia replacement with diverse application scenarios, which potentially opens up a window on treating microglia-associated CNS disorders. [Display omitted] •mrBMT and mrPB achieve nonself microglia replacement at the CNS-wide scale•mrMT allows foreign microglia to replace endogenous cells at the specified brain region•mrBMT and mrPB cells are derived from CCR2-positive BMCs and PBCs, respectively•mrBMT and mrPB cells are more macrophage-like, while mrMT cells are more microglia-like The bottleneck for microglia-based gene therapy is the lack of tools for genetic manipulation of microglia and/or their allotransplantation. In this study, Xu et al. develop three strategies achieving efficient microglia replacement at the CNS-wide scale or specific brain regions of interest. Each approach has its own advantages and application scenarios.